The present invention relates to novel substituted quinolines and isoquinolines thereof useful as pharmaceutical agents, to methods of their production, compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel compounds of the present invention are useful in the treatment of neurological disorders such as traumatic brain injury, cerebral ischemia, stroke, migraine, acute and chronic pain, epilepsy, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, and depression. The compounds may also be useful for the treatment of nonneurological disorders such as asthma.
The entry of excessive amounts of calcium ion into neurons following an ischemic episode or other neuronal trauma has been well documented. Uncontrolled high concentrations of calcium in neurons initiates a cascade of biochemical events that disrupt normal cellular processes. Among these events are the activation of proteases and lipases, breakdown of neuronal membranes and the formation of free radicals which may ultimately lead to cell death. In particular, the selective N-type calcium channel blocker, SNX-111, has demonstrated activity in a number of models of ischemia and pain (Bowersox S. S., et al., Drug News and Perspective, 1994;7:261-268 and references cited therein).
Therefore, compounds which block N-type calcium channels may be useful in the treatment of neurological disorders such as traumatic brain injury, stroke, migraine, acute and chronic pain, epilepsy, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, and depression.